FAK loss reduces BRAF^V600E-induced ERK phosphorylation to promote intestinal stemness and cecal tumor formation.

Abstract

<i>BRAF</i>^V600E mutation is a driver mutation in the serrated pathway to colorectal cancers. BRAF^V600E drives tumorigenesis through constitutive downstream extracellular signal-regulated kinase (ERK) activation, but high-intensity ERK activation can also trigger tumor suppression. Whether and how oncogenic ERK signaling can be intrinsically adjusted to a 'just-right' level optimal for tumorigenesis remains undetermined. In this study, we found that FAK (Focal adhesion kinase) expression was reduced in <i>BRAF</i>^V600E-mutant adenomas/polyps in mice and patients. In <i>Vil1-Cre;BRAF</i>^LSL-V600E/+;<i>Ptk2</i>^fl/fl mice, <i>Fak</i> deletion maximized BRAF^V600E's oncogenic activity and increased cecal tumor incidence to 100%. Mechanistically, our results showed that Fak loss, without jeopardizing BRAF^V600E-induced ERK pathway transcriptional output, reduced EGFR (epidermal growth factor receptor)-dependent ERK phosphorylation. Reduction in ERK phosphorylation increased the level of Lgr4, promoting intestinal stemness and cecal tumor formation. Our findings show that a 'just-right' ERK signaling optimal for <i>BRAF</i>^V600E-induced cecal tumor formation can be achieved via Fak loss-mediated downregulation of ERK phosphorylation.